Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis.

Abstract

BACKGROUND:

Infection with Helicobacter pylori, a high-risk factor for gastric cancer, is frequently associated with chronic inflammation through activation of nuclear factor κB (NF-κB). Trefoil factor 1 (TFF1) is a constitutively expressed protein in the stomach that has tumor-suppressor functions and plays a critical role in maintaining mucosal integrity. This study investigated the role of TFF1 in regulating the proinflammatory response to H. pylori infections.

METHODS:

For in vitro studies, immunofluorescence, luciferase reporter assays, Western blots, and quantitative real-time polymerase chain reaction were performed to investigate the activation of NF-κB and its target genes in response to infections with H. pylori strains J166 and 7.13. In addition, Tff1-knockout (KO) and Tff1-wild-type mice were used for infections with the H. pylori strain called premouse Sydney strain 1.

RESULTS:

The reconstitution of TFF1 expression in gastric cancer cells significantly suppressed H. pylori-mediated increases in NF-κB-p65 nuclear staining, transcriptional activity, and expression of proinflammatory cytokine genes (tumor necrosis factor α, interleukin 1β, chemokine [C-X-C motif] ligand 5, and interleukin 4 receptor) that were associated with reductions in the expression and phosphorylation of NF-κB-p65 and IκB kinase α/β proteins. The in vivo studies using the Tff1-KO mouse model of gastric neoplasia confirmed the in vitro findings. Furthermore, they demonstrated increases in chronic inflammation scores and in the frequency of invasive gastric adenocarcinoma in the Tff1-KO mice infected with H. pylori versus the uninfected Tff1-KO mice.

CONCLUSIONS:

These findings underscore an important protective role of TFF1 in abrogating H. pylori-mediated inflammation, a crucial hallmark of gastric tumorigenesis. Therefore, loss of TFF1 expression could be an important step in H. pylori-mediated gastric carcinogenesis.

• Authors: Mohammed Soutto, Zheng Chen, Ahmed M Katsha, Judith Romero-Gallo, Uma S Krishna, M Blanca Piazuelo, M Kay Washington, Richard M Peek Jr, Abbes Belkhiri, Wael M El-Rifai
• Journal: Cancer (Cancer) Vol. 121 Issue 24 Pg. 4348-58 (Dec 15 2015) ISSN: 1097-0142 [Electronic] United States
• PMID: 26372254 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 American Cancer Society.

Chemical References

• Chemokine CXCL5
• Interleukin-1beta
• Peptides
• Receptors, Interleukin-4
• Tff1 protein, mouse
• Transcription Factor RelA
• Trefoil Factor-1
• Tumor Necrosis Factor-alpha
• I-kappa B Kinase

Topics

• Adenocarcinoma (genetics, immunology, microbiology)
• Animals
• Carcinogenesis (genetics)
• Chemokine CXCL5 (immunology)
• Gastric Mucosa (immunology, metabolism, microbiology)
• Helicobacter Infections (genetics, immunology)
• Helicobacter pylori
• Humans
• I-kappa B Kinase (metabolism)
• In Vitro Techniques
• Inflammation
• Interleukin-1beta (immunology)
• Mice
• Mice, Knockout
• Peptides (genetics)
• Phosphorylation
• Real-Time Polymerase Chain Reaction
• Receptors, Interleukin-4 (immunology)
• Stomach (immunology, microbiology)
• Stomach Neoplasms (genetics, immunology, microbiology)
• Transcription Factor RelA (metabolism)
• Trefoil Factor-1
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (immunology)